Cervix

Cervix

1. UTERINE CERVIX
Dr. Saumya, Dept of Pathology, SIMS
www.shadan.in

2. Anatomy

3. Squamo columnar junction

4. Normal cervix [gross] - nulliparous woman

5. Normal ectocervical epithelium - stratified squamous

6. Production of estrogens by ovary stimulates
maturation of the cervical and vaginal squamous
mucosa and formation of intracellular glycogen
vacuoles in the cells
Glycogen provides a substrate for various
endogenous vaginal aerobes and anaerobes, but
particularly lactobacilli, which are the dominant
microbial species in the normal vagina
Lactobacilli produce lactic acid, which maintains
the vaginal pH below 4.5, suppressing the growth
of other saprophytic and pathogenic organisms

7. Inflammatory conditions

8. INFLAMMATIONS:
ACUTE & CHRONIC CERVICITIS:
Gonococci,
Chlamydiae,
Mycoplasmas,
Herpes virus [type 2],
Tuberculosis,
[sterility]

9. Cervicitis

10. Cervicitis
Marked cervical inflammation
produces reparative and reactive
changes of the epithelium and
shedding of atypical-appearing
squamous cells, and therefore may
cause an abnormal Pap test result

11. Endocervical polyps

12. Endocervical polyps:
2 to 5 % of adult women
Common benign exophytic growths that arise
within the endocervical canal
CLINICAL FEATURES: Irregular vaginal ‘
spotting’
GROSS: small, sessile “bumps” to large
polypoid masses
MICRO: dense fibrous stroma covered with
endocervical epithelium
Simple curettage OR excision.

13. Cervical cancer and cervical
intraepithelial neoplasia ( CIN )

14. Worldwide, cervical carcinoma is the third
most common cancer in women
remarkable benefits of effective screening,
early diagnosis, and curative therapy

15. Risk factors
The risk factors for cervical cancer are related
to both host and viral characteristics such as
HPV exposure, viral oncogenicity, inefficiency
of immune response, and presence of co-
carcinogens

16. Major risk factors:
1. Early age at first sexual
intercourse,
2. Multiple sexual partners
3. Male partner with previous
multiple sexual partners
Sexually
transmitted
agent ---
HPV
Risk factors

17. Other risk factors:
Oral contraceptives,
Cigarette smoking,
Parity,
Family history,
Genital infections,
Lack of circumcision of male
partner - smegma

18. Human Papilloma Virus [HPV]
Vulvar condyloma acuminatum,
Vulvar & vaginal squamous cell
carcinomas,
85% cervical cancers,
90% condylomata & precancerous lesions;
DNA virus

19. Pathogenesis
High-risk types -- > carcinoma,
- 16, 18, 31, 33,
- Transform cells in tissue culture,
- Viral DNA integrated with host DNA,
Low-risk types -->condyloma acuminatum
--- 6, 11, 42 & 44,
- Episomal viral DNA;

20. HPV
Infect immature basal cells of the squamous
epithelium
Mature cells are arrested in the G1 phase of
the cell cycle, but they continue to actively
progress through the cell cycle when infected
with HPV, which uses the host cell DNA
synthesis machinery to replicate its own
genome

22. SQUAMOUS
DIFFERENTIATION
Infection
basal cells
Early (Non-structural)
protein synthesis
LATENTLATENT
INFECTIONINFECTION
Condyloma
or CIN-1
[koilocytosis]
Integration[ISH]
+ Oncogenes
- Tumour suppressor genes
INVASIVE
CARCINOMA
Productive
DNA synthesis
Late [capsid]Late [capsid]
protein synthesisprotein synthesis
[IH][IH]
Viral
particles [EM]
DesquamationDesquamation
transmissiontransmission
HPV life cycle
Episomal DNA
replication (ISH)

24. Pathogenesis
E6 protein promotes

upregulates telomerase and bind to p53
promote its degradation
E7 protein binds the hypophosphorylated
(active) form of RB and promotes its
degradation via the
proteasome pathway,

25. Uninfected
cell
infected
cell

26. Deregulation of restriction point R by
HPV 16 E7

27. Cervical cancer and HPV
infection

28. Cytopathic effects of HPV
Nuclear enlargement, nuclear
pyknosis or
hyperchromaticity,
anisocytosis, multinucleation,
and
perinuclear cytoplasmic
vacuolization
(a) Histological features of a
lesion is classified as LSIL

(b) Cytological features of
LSIL

29. Electron microscopy
(a) intranuclear
aggregates of HPV
in a koilocytotic,
superficial cell of an
HSIL. The
marginated nuclear
chromatin is
agglutinated,
cytoplasmic
substance displays
vacuolar
degeneration (vd)-
koilocytotic
ballooning on light
microscopy
(b) Higher
magnification

30. Koilocytes – perinuclear halo caused by E5 that localizes to the membranes of the
endoplasmic reticulum.

31. Cervical Intraepithelial Neoplasia
(CIN)
Precancerous lesions
Cervical cancer3 to 20 yrs.
( can be diagnosed by pap smear)
1. Continuum of changes
2. Not invariably progress to cancer
3. Associated with HPV

32. SQUAMOUS CELL
CARCINOMA

34. Pathogenesis
of cervical
neoplasia
Sexual activity
HPV exposure
Cervical transformation zone
Ectocervix Squamous epithelium
Low grade
Low-risk HPVs
6,11,42-44,
High grade
High-risk HPVs
16,18,31,33,35
Smoking , oral contraceptives, high parity, altered
immune status, host gene alterations, time
Endocervical columnar epithelium
Glandular intraepithelial lesion
(adenocarcinoma-in-situ)
High-risk HPVs
INVASIVE SQUAMOUS CARCINOMA ADENOCARCINOMA
rare

35. The diagnosis of SIL is based on
identification of nuclear atypia
characterized by nuclear
enlargement, hyperchromasia (dark
staining), coarse chromatin granules,
and variation in nuclear size and
shape

38. The grading of SIL into low or high grade is
based on expansion of the immature cell layer
from its normal, basal location
LSIL does not progress directly to invasive
carcinoma and in fact most cases regress
spontaneously; only a small percentage
progress to HSIL

39. Chronic cervicitis with dysplasia

40. Chronic cervicitis with moderate dysplasia [ CIN - II ]

41. Carcinoma cervix - Morphology
Gross: - Fungating ( Exophytic ),
- Ulcerative,
- Infiltrative;
Micro:
.. Squamous cell carcinomas --- 75 - 90% ,
* 95% - large cell type,
* 5% - Small cell undifferentiated,
.. Adenocarcinomas
.. Adenosquamous carcinomas
.. Undifferentiated carcinomas 10 to
25%

42. Carcinoma, cervix - gross

43. Carcinoma, cervix involving the vagina

44. Carcinoma, cervix infiltrating the uterine corpus

47. LSIL H & EISH for HPV DNA Ki67 p16INK4 IHC

48. Clinical course:
Asymptomatic,
Irregular vaginal bleeding or
bleeding on touch,
Leukorrhea,
Dysuria;

49. Diagnosis
Pap test( Cervical cytology)
–to detect epithelial cell abnormalities
Colposcopy
Cervical biopsies:
•Colposcopic biopsies
•Endocervical curettage
•Cone biopsy

50. The pap test
The Pap test is considered by many to be the
most cost effective cancer reduction program
ever devised
1928- George N. Papanicolaou
1940s- screening
programmes started

53. Screening methods

54. Approximate lifetime risks of acquiring
HPV & Death by cervical cancer:
HPV
HPV
75%
Population
50%
High-risk
HPV 10%
Persistent
High-grade
CIN
1. 3%
Invasive
Carcinoma
0. 4%
DEATH

55. Prognosis:
5 - year survival rate:
Stage - I = 80 to 90 %,
Stage - II = 75%,
Stage - III = 35% ,
Stage - IV = 10 to 15%.

56. Gardasil (Merck & Co., Inc.)-
quadrivalent- HPV 6, 11, 16,18
Cervarix (GlaxoSmithKline)-
bivalent - HPV 16 and 18
They have shown extraordinary
efficacy in preventing type-specific
histologic CIN 2,3 lesions
Administered in three doses to
females ages 9 to 26 years before
the initiation of sexual activity

57. Summary
HPV
VACCIN
E
PAP
SMEAR
VIA &
VILI
SURGER
Y &
RADIOTH
ERAPY

58. WHO comprehensive cancer
prevention and control
Primary prevention- Education to reduce high-risk sexual
behavior to limit HPV transmission/acquisition
Delay age of first sexual intercourse
Condom use, limit number of partners, change in sexual
behavior
HPV vaccination
Early detection (secondary prevention)
Screening: Identify and treat precancerous lesions before
they progress to cervical cancer
Early diagnosis: Identify and treat early cancer while the
chance of cure is still good (reduces cervical cancer mortality)
Tertiary prevention:
Treatment of invasive cancer
Palliative care
Health System strengthening

59. Normal
cervical
epithelium
Pre-cancerous
lesions
Eliminated
lesion
Clinical invasive
cervical cancer
Death from cvx
cancer
Cure
+Sexual promiscuity
-HPV
-(HS II)
-(Trichomonas vaginalis)
-(HIV)
-.......
+Smoking
+Hormonal contraception
+Age
+Cohortphenomena
+HPV vaccination
RISK FACTORS
PROTECTIVE FACTORS
Screening
Follow-up
Treatment
+Participation screening
+Frequency screening
+Targetpopulation
+Quality screentest
+Follow-up/treatment-strategy
+Compliance follow-up/treatment
Primary prevention
Secondary prevention
Cancer
treatment
+ Early consultation & diagnosis
+ Phase
+ Therapy
+ Age
SURVIVAL
Preclinical
invasive cancer